In vitro leukemic cell lines now exist which express a variety of type-specific functions characteristic of normal hematopoietic cells, including induction of differentiated properties by humoral regulators. The cell lines themselves produce regulatory molecules that mediate specific stimulatory or inhibitory actions on hematopoiesis, as well as on the functions of normal mature end cells. The complexity of hematopoietic regulation requires a multiparameter analysis and purified cell preparations in order to understand the functional properties of leukemic cells. The properties of leukemic cells. The objectives of this proposal are to establish cell lines of human and mouse leukemias, to define the phenotypes of leukemic cells, to study their retention of responsiveness to regulatory control and activation of functions, to assay for the production of molecules stimulating or inhibiting normal cell functions, and to determine differential sensitivity of leukemic cells to toxicity or growth inhibition by cell type-specific drugs. Primary cultures and established lines of leukemic cells will be assayed for production of lysosomal enzymes, myeloid colony-stimulating activity, lymphocyte activation factors and prostaglandins; for T lymphocyte-specific terminal transferase and malignant lymphoid enzyme N-alkaline phosphatase; for immunoglobulin, surface receptors and antigens characteristic of a blood cell lineage; for a soluble inhibitor of normal hematopoiesis found in leukemic patients; and for nonspecific and antibody-dependent phagocytosis and cell-mediated cytotoxicity. The response of these cells to macrophage and lymphocyte-activating substances will be tested for inhibition of cell proliferation in parallel with induction of differentiated surface markers and functional properties. A culture system supporting continuous marrow stem cell proliferation will also be used in which spontaneous and viral leukemogenesis has been demonstrated. Certain chemotherapeutic drugs will be tested in vitro for subtype-specific toxicity. The emphasis of the program will be directed at improvements in diagnosis, defining regulatory derangements in leukemia, and determining the interactions between normal and leukemic cells.